Abstract
BackgroundThe α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. The goal of this study was to evaluate the two carbon-11-labeled α7 nAChR agonists [11C]A-582941 and [11C]A-844606 for their potential as novel positron emission tomography (PET) tracers.Methodology/Principal FindingsThe two tracers were synthesized by methylation of the corresponding desmethyl precursors using [11C]methyl triflate. Effects of receptor blockade in mice were determined by coinjection of either tracer along with a carrier or an excess amount of a selective α7 nAChR agonist (SSR180711). Metabolic stability was investigated using radio-HPLC. Dynamic PET scans were performed in conscious monkeys with/without SSR180711-treatment. [11C]A-582941 and [11C]A-844606 showed high uptake in the mouse brain. Most radioactive compounds in the brain were detected as an unchanged form. However, regional selectivity and selective receptor blockade were not clearly observed for either compound in the mouse brain. On the other hand, the total distribution volume of [11C]A-582941 and [11C]A-844606 was high in the hippocampus and thalamus but low in the cerebellum in the conscious monkey brain, and reduced by pretreatment with SSR180711.Conclusions/SignificanceA nonhuman primate study suggests that [11C]A-582941 and [11C]A-844606 would be potential PET ligands for imaging α7 nAChRs in the human brain.
Highlights
IntroductionThe nicotinic acetylcholine receptors (nAChRs) are ligandgated ion channels that are distributed throughout the human central nervous system (CNS) and that each consist of five subunits (a combination of a and b subunits)
The nicotinic acetylcholine receptors are ligandgated ion channels that are distributed throughout the human central nervous system (CNS) and that each consist of five subunits
These subtypes are best characterized in terms of their ligand selectivity, since they can be studied by means of binding techniques: [3H]cytisine or [3H]nicotine can label a4b2 nicotinic acetylcholine receptors (nAChRs), and [125I]a-bungarotoxin or [3H]methyllycaconitine ([3H]MLA) is used to label a7 nAChRs [3]
Summary
The nicotinic acetylcholine receptors (nAChRs) are ligandgated ion channels that are distributed throughout the human central nervous system (CNS) and that each consist of five subunits (a combination of a and b subunits). Among the several nAChRs subtypes in the CNS, the homomeric a7 and heteromeric a4b2 subtypes are predominant in the brain [2]. These subtypes are best characterized in terms of their ligand selectivity, since they can be studied by means of binding techniques: [3H]cytisine or [3H]nicotine can label a4b2 nAChRs, and [125I]a-bungarotoxin or [3H]methyllycaconitine ([3H]MLA) is used to label a7 nAChRs [3]. The goal of this study was to evaluate the two carbon-11-labeled a7 nAChR agonists [11C]A-582941 and [11C]A-844606 for their potential as novel positron emission tomography (PET) tracers
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